AB0152 URIC ACID IN SYSTEMIC SCLEROSIS-RELATED PULMONARY ARTERIAL HYPERTENSION:INNOCENT BYSTANDER OR COVERT ACCOMPLICE?
Authors: A. Van Caam, J. Lemmers, M. Vonk, S. Van Leuven
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> When uric acid levels increase to reach the supersaturation level (&gt;70 μg/ml), it transforms into its crystalline form and binds to surface lipids on immune cells. Phagocytes ingest this cellular debris and thereby receive a 'danger signal' from uric acid and are stimulated to mature and become immunostimulatory [1,2]. <h3>Objectives</h3> Considering uric acid helps to predict the development of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) (3), we aim to establish whether uric acid induces a pro-inflammatory response in SSc in general and in SSc-PAH in particular. <h3>Methods</h3> Peripheral blood mononuclear cells (PBMCs) were harvested from 16 SSc-PAH patients. PMBCs were isolated from 32 age- and sex-matched SSc-nonPAH patients with similar skin distribution and autoantibodies. Finally, PMBCs from 5 idiopathic PAH (iPAH) patients and 16 age- and sex- matched healthy controls were collected. Cells were treated with or without uric acid in soluble form for 24 hours, and subsequently cytokine production was measured by Luminex, and mRNA levels were assessed using qPCR. <h3>Results</h3> Baseline expression of interleukin (IL)-1β and IL-6 was similar in SSc-PAH, SSc-nonPAH, iPAH and healthy controls. On mRNA level, urid acid stimulated IL-1 and IL-6 expression in all PBMCs but IL-1 and IL-6 expression was most potently upregulated in SSc patients compared to healthy controls (a 2-fold versus an 8-fold increase respectively). However, induction of IL-1 and IL-6 expression by urid acid-stimulated PBMCs was similar in SSc-PAH and SSc-nonPAH patients. Similarly, on protein level, production of IL-1β, IL-6 and TNF-α was increased in PBMCs from SSc patients compared to iPAH patients and healthy controls. Interestingly, we observed that urid-acid stimulated PBMCs from SSc-PAH patients produced significantly more IL-1β, IL-6 and TNF-α compared to SSc-nonPAH patients. <h3>Conclusion</h3> In this study we demonstrate that soluble uric orchestrates an excessive inflammatory response by facilitating more enhanced IL-1β, IL-6 and TNF-α production in SSc-PAH compared to SSc-nonPAH, iPAH and healthy controls. These findings suggest that uric acid not only has a role in prediction of SSc-PAH but also contributes to the development of SSc-PAH. <h3>References</h3> [1]Shi Y. Caught red-handed: uric acid is an agent of inflammation. J Clin Invest. 2010 Jun;120(6):1809-11. [2]Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425(6957):516–521. [3]Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, Khanna D, Müller-Ladner U, Pope JE, Vonk MC, Doelberg M, Chadha-Boreham H, Heinzl H, Rosenberg DM, McLaughlin VV, Seibold JR; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014 Jul;73(7):1340-9. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Arjan van Caam: None declared, Jacqueline Lemmers: None declared, Madelon Vonk Speakers bureau: Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, MSD, Novartis and Roche, Consultant of: Boehringer Ingelheim and Janssen, Grant/research support from: Boehringer Ingelheim, Janssen, Ferrer and Galapagos, Sander van Leuven: None declared.